Niacin (nicotinic acid) is one of the most effective hypolipidemic agents available. However, its use is greatly limited by side effects, the most prominent of which is intense flushing. We recently demonstrated that niacin induced vasodilation is mediated by a release of prostaglandin (PG) D2. An intriguing discovery was made that pretreatment with a very low dose of aspirin (40 mg) essentially totally inhibits niacin-induced release of PGD2 in vivo. We have obtained a considerable body of preliminary evidence that suggests strongly that tissue macrophages are the cellular source of niacin-induced release of PGD2 in vivo and that PG production by macrophages can be inhibited by very low doses of aspirin. Studies are now proposed to establish more definitively the cells that are activated by niacin in vivo. In particular, resident tissue macrophages isolated from various tissues of guinea pigs and humans will be studied. Experiments will then focus on identifying potential cellular mechanisms involved in niacin induced activation of arachidonic acid metabolism. Studies will then be carried out to determine the molecular basis for the unusual sensitivity of PG production in niacin responsive cells to inhibition by aspirin. Specifically we will address whether this enhanced sensitivity is related to (a) the cyclooxygenase(s) present in these cells, (b) the mechanism by which aspirin inhibits PG biosynthesis, or (c) the intracellular metabolic rate of aspirin. Finally, the effect of treatment of normal volunteers with pharmacologic doses of prednisone on niacin-induced release of eicosanoids in vivo will be determined. The finding that very low doses of aspirin can inhibit niacin-induced release of PGD2 in humans has important therapeutic implications for the use of niacin as a hypolipidemic agent. Further, these studies should provide valuable insights into cell-specific mechanisms involved in activation of arachidonic acid metabolism and factors that can influence the ability of certain pharmacologic agents to inhibit PG biosynthesis in specific cell types.